Much attention has been given to the recognition and treatment of the many infants who develop neonatal abstinence syndrome from in utero exposure to illicit drugs of abuse: specifically opioids and benzodiazepines. However, thousands of critically ill infants (and children) are also exposed to opioids and benzodiazepines to achieve sedation and analgesia as part of routine care in neonatal and pediatric intensive care units. While the use of these agents are undisputedly beneficial in reducing pain and anxiety, improving ventilation, reducing pulmonary vascular resistance and improving outcomes;the consequence is often the development of tolerance and physiologic dependence - similar to in utero exposure from these same classes of drugs. In fact, between 10-90% of infants and children who are treated for more than 5 days with opioids and/or benzodiazepines will develop symptoms of withdrawal when the drug is reduced or discontinued to facilitate the child's care. Thus, an effective detoxification or "tapering" regime is necessary to properly restore counter adaptative cellular events, to minimize a harmful stress response, and to achieve homeostasis. Similar to the current standard of care for infants with in utero drug dependence, the slow tapering of the drug or the addition of an alternative class of drugs is necessary. Unfortunately, the slow tapering often prolongs hospitalization and increases the cost of care. We have recently reported the results of randomized placebo control trial showing that the addition of clonidine (12-adrenergic agonist) to tapering doses of opioids was efficacious and safe in treating opioid dependence in infants who had moderate to severe neonatal abstinence syndrome from in utero exposure to opioids. Currently, we propose to perform a double-blinded, randomized placebo-control trial at Johns Hopkins Hospital in a cohort of critically ill infants requiring mechanical ventilation and sedation, but who have not been exposed in utero to opioids or benzodiazepines. The overall hypothesis is that early addition of clonidine to this cohort, known to be at risk for developing iatrogenic physical dependence and NAS, will be safe and efficacious in reducing the time to complete sedative and analgesic drug detoxification. The hypothesis will be tested by addressing 2 specific aims that will determine: 1) the efficacy and safety of clonidine in critically ill infants, and 2) pharmacokinetics and pharmacodynamics using population-based pharmacokinetics in this vulnerable infant population who have only been exposed to these drugs as part of their routine care. Many "standard of care practices" are incorporated in neonatal and pediatric care prior to evidence based studies. This proposal will fill a much needed gap in translating what we have learned about basic mechanisms mediating dependence and withdrawal to proven therapies for vulnerable pediatric populations. PUBLIC HEALTH RELEVANCE: Critically ill infants who are on breathing machines with major illnesses are rountinely exposed to high concentrations of opioids and sedatives manage pain and sedation. Similar to babies who are exposed these types of drugs before birth, these critically ill babies can also develop drug withdrawal requiring treatment and extending hospitalization. We propose to do a clinical study to determine whether adding another medication (clonidine) to help with the management of pain and sedation will decrease the development of drug withdrawal in this group of babies.